This project deals with immune control of cowpox virus (CPXV), a member ofthe medically important orthopoxvirus genus. CPXV causes zoonotic infections, is endemic in rodent populations, and has the largest repertoire of immune evasion genes. The project is based on published work and preliminary data from the applicant's laboratory on CD8+ T and natural killer (NK) cell control of CPXV infections in mice. The applicant's laboratory showed that CPXV encodes two open reading frames (ORFs) that inhibit major histocompatibility complex (MHC) class I (MHC-I) expression on infected cells. Deletion of these ORFs resulted in attenuated CPXV virulence due to CD8+ T cell control, the first clear-cut example of the role of viral MHC-I inhibition in in vivo infections. T cell priming is not affected but virus-specific CD8+ T cell effector responses are blocked by MHC-I inhibition, providing opportunities for further study of virus-specific CD8+ T cell responses. In addition, the applicant's lab showed that NK cells are recruited to the draining LN following CPXV infection. They showed this was dependent on interferon-gamma which induces the chemokines CXCL9 and CXCL10 and CXCR3-expressing NK cells. However, NK cells are inhibited by CPXV from producing interferon-gamma. In this project, they plan to address the following Specific Aims to further study: 1) CD8+ T cell responses to CPXV; 2) CPXV-dependent recruitment of NK cells; and 3) Novel . immunomodulatory CPXV ORFs. Ongoing and planned experiments will be done in collaboration with other principal investigators in this U19 application. In addition, human transiational studies are planned. Thus, these studies will provide new insight into how the innate and adaptive immune systems control viruses, such as CPXV.